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Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung injury in dogs.
J Surg Res. 1999 Dec; 87(2):152-63.JS

Abstract

BACKGROUND

To assess the effects of gabexate mesilate (FOY), a protease inhibitor, on a canine model of pulmonary ischemia-reperfusion injury. FOY has been applied clinically to treat acute pancreatitis and disseminated intravascular coagulation (DIC) and has been found to suppress some leukocyte-mediated tissue injuries in both in vitro and in vivo studies.

DESIGN

Comparison of four experimental groups: group 1 (untreated control, n = 8), unilateral (left) pulmonary ischemia due to perfusion and ventilation obstruction followed by reperfusion, without receiving any specific treatment; group 2 (negative control, sham operation, n = 8), left pulmonary hilar dissection without ischemia; group 3 (FOY posttreatment, n = 8), FOY treatment during the reperfusion stage only; and group 4 (FOY pretreatment, n = 8), FOY treatment before ischemia and then continued during reperfusion.

SETTING

University animal laboratory.

SUBJECTS

Heart-worm-free mongrel dogs (12 to 15 kg body wt) were anesthetized with pentobarbital and mechanically ventilated.

INVESTIGATIONS

Lung ischemia was made by snaring the left pulmonary artery and veins and clamping the bronchus with peribronchial tissue for 90 min followed by reperfusion for 18 h. Animals of the two treatment groups received a 1 mg/kg bolus of FOY at the beginning of reperfusion, with infusion of 2 mg/kg/h of FOY continuously starting 30 min before ischemia (group 4) or after reperfusion (group 3). During this study the following were measured: hemodynamics and aerodynamics, blood gas, bronchoalveolar lavage (BAL) fluid neutrophil percentage and protein concentration, lung wet to dry weight ratio (W/D ratio), myeloperoxidase (MPO) activity of the lung tissue, alveolar neutrophil infiltration, and degree of injury.

RESULTS

This model of lung ischemia-reperfusion induced significant pulmonary hypertension, increased pulmonary vascular resistance, decreased pulmonary dynamic compliance and arterial hypoxemia, increased BAL fluid total protein amount and neutrophil percentage, and increased alveolar neutrophil infiltration, histological injury score, and lung tissue MPO assay (group 1). Animals of the sham operation (negative control, group 2) showed only minimal changes in the above parameters. Treatment with FOY significantly attenuated the injury by decreasing the lung W/D ratio, alveolar neutrophil infiltration, histological injury score, lung tissue MPO assay, BAL fluid neutrophil percentage, and protein amount. Pretreatment with FOY (group 4) attenuated the injury to a significantly greater degree than it did when administered at the reperfusion stage only (group 3), which was reflected by the above-mentioned parameters, and as well significantly improved gas exchange function. FOY treatment was found to have little effect in altering hemodynamics and aerodynamics at most time points in this model of lung injury.

CONCLUSIONS

FOY can attenuate the ischemia-reperfusion-induced acute lung injury in dogs by ameliorating the degree of alveolar membrane permeability change, neutrophil aggregation, and activation. FOY treatment starting before ischemia attenuated this injury to a significantly higher degree than its use after ischemia. However, the effect of FOY may be partial because it cannot alter the hemodynamics or aerodynamics as prominently as other parameters in this type of lung injury. Concomitant use of FOY with other agents will have additive or synergic effects in preventing lung ischemia-reperfusion injury.

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Publisher Full Text

Authors+Show Affiliations

Luh SP
Department of Surgery, National Taiwan University Hospital and School of Medicine, Taipei, Republic of China.
Tsai CC
No affiliation info available
Shau WY
No affiliation info available
Chen JS
No affiliation info available
Kuo SH
No affiliation info available
Lin-Shiau SY
No affiliation info available
Lee YC
No affiliation info available

MeSH

AnimalsBronchoalveolar Lavage FluidDogsGabexateHemodynamicsIschemiaLungNeutrophilsPeroxidaseReperfusion InjuryRespiratory Distress SyndromeSerine Proteinase Inhibitors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10600344

Citation

Luh, S P., et al. "Effects of Gabexate Mesilate (FOY) On Ischemia-reperfusion-induced Acute Lung Injury in Dogs." The Journal of Surgical Research, vol. 87, no. 2, 1999, pp. 152-63.
Luh SP, Tsai CC, Shau WY, et al. Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung injury in dogs. J Surg Res. 1999;87(2):152-63.
Luh, S. P., Tsai, C. C., Shau, W. Y., Chen, J. S., Kuo, S. H., Lin-Shiau, S. Y., & Lee, Y. C. (1999). Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung injury in dogs. The Journal of Surgical Research, 87(2), 152-63.
Luh SP, et al. Effects of Gabexate Mesilate (FOY) On Ischemia-reperfusion-induced Acute Lung Injury in Dogs. J Surg Res. 1999;87(2):152-63. PubMed PMID: 10600344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung injury in dogs. AU - Luh,S P, AU - Tsai,C C, AU - Shau,W Y, AU - Chen,J S, AU - Kuo,S H, AU - Lin-Shiau,S Y, AU - Lee,Y C, PY - 1999/12/22/pubmed PY - 1999/12/22/medline PY - 1999/12/22/entrez SP - 152 EP - 63 JF - The Journal of surgical research JO - J Surg Res VL - 87 IS - 2 N2 - BACKGROUND: To assess the effects of gabexate mesilate (FOY), a protease inhibitor, on a canine model of pulmonary ischemia-reperfusion injury. FOY has been applied clinically to treat acute pancreatitis and disseminated intravascular coagulation (DIC) and has been found to suppress some leukocyte-mediated tissue injuries in both in vitro and in vivo studies. DESIGN: Comparison of four experimental groups: group 1 (untreated control, n = 8), unilateral (left) pulmonary ischemia due to perfusion and ventilation obstruction followed by reperfusion, without receiving any specific treatment; group 2 (negative control, sham operation, n = 8), left pulmonary hilar dissection without ischemia; group 3 (FOY posttreatment, n = 8), FOY treatment during the reperfusion stage only; and group 4 (FOY pretreatment, n = 8), FOY treatment before ischemia and then continued during reperfusion. SETTING: University animal laboratory. SUBJECTS: Heart-worm-free mongrel dogs (12 to 15 kg body wt) were anesthetized with pentobarbital and mechanically ventilated. INVESTIGATIONS: Lung ischemia was made by snaring the left pulmonary artery and veins and clamping the bronchus with peribronchial tissue for 90 min followed by reperfusion for 18 h. Animals of the two treatment groups received a 1 mg/kg bolus of FOY at the beginning of reperfusion, with infusion of 2 mg/kg/h of FOY continuously starting 30 min before ischemia (group 4) or after reperfusion (group 3). During this study the following were measured: hemodynamics and aerodynamics, blood gas, bronchoalveolar lavage (BAL) fluid neutrophil percentage and protein concentration, lung wet to dry weight ratio (W/D ratio), myeloperoxidase (MPO) activity of the lung tissue, alveolar neutrophil infiltration, and degree of injury. RESULTS: This model of lung ischemia-reperfusion induced significant pulmonary hypertension, increased pulmonary vascular resistance, decreased pulmonary dynamic compliance and arterial hypoxemia, increased BAL fluid total protein amount and neutrophil percentage, and increased alveolar neutrophil infiltration, histological injury score, and lung tissue MPO assay (group 1). Animals of the sham operation (negative control, group 2) showed only minimal changes in the above parameters. Treatment with FOY significantly attenuated the injury by decreasing the lung W/D ratio, alveolar neutrophil infiltration, histological injury score, lung tissue MPO assay, BAL fluid neutrophil percentage, and protein amount. Pretreatment with FOY (group 4) attenuated the injury to a significantly greater degree than it did when administered at the reperfusion stage only (group 3), which was reflected by the above-mentioned parameters, and as well significantly improved gas exchange function. FOY treatment was found to have little effect in altering hemodynamics and aerodynamics at most time points in this model of lung injury. CONCLUSIONS: FOY can attenuate the ischemia-reperfusion-induced acute lung injury in dogs by ameliorating the degree of alveolar membrane permeability change, neutrophil aggregation, and activation. FOY treatment starting before ischemia attenuated this injury to a significantly higher degree than its use after ischemia. However, the effect of FOY may be partial because it cannot alter the hemodynamics or aerodynamics as prominently as other parameters in this type of lung injury. Concomitant use of FOY with other agents will have additive or synergic effects in preventing lung ischemia-reperfusion injury. SN - 0022-4804 UR - https://www.unboundmedicine.com/medline/citation/10600344/Effects_of_gabexate_mesilate__FOY__on_ischemia_reperfusion_induced_acute_lung_injury_in_dogs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-4804(99)95730-X DB - PRIME DP - Unbound Medicine ER -